Abstract: Cryptococcus neoformans is a major comorbidity of HIV infection and transplantation with high mortality rates due to the toxicity and limited availability and efficacy of existing antifungal agents. As an environmental saprophyte, cryptococcal pathogenesis requires adaptation to the environment of the human host. Our work has led us to the scientific premise that stress adaptation in C. neoformans requires two sequential post- transcriptional events. First, the accelerated degradation mRNAs encoding metabolically expensive processes such as the translational machinery, and second, the translation of stress response mRNAs via cap- independent translation mechanisms on recycled ribosomes. This premise implicates the ribosome as a sensor of cellular stress through translation quality control mechanisms. The aims in this proposal will investigate co- translational quality control as a trigger for accelerated mRNA degradation in response to temperature sturess (Aim1) and will investigate cap-independent translation mechanisms (Aims 2) in stress adaptation. Aim 2 will focus on two CNBP orthologues expressed in C. neoformans that we hypothesize to regulate translation via internal ribosome entry sites (IRES) in response to temperature and oxidative stress. Finally, we will assess the contributing role of ribosome-associated quality control in starvation stress responsive translation and define the contributions of each quality control pathway in the response of C. neoformans to compound stressors (Aim 3). These studies will be the first investigation of translation in C. neoformans, and include the first application of ribosome profiling in this pathogen. Translation is known to be pharmacologically targetable but conservation in eukaryotes is thought to be a hindrance. Only through molecular investigation of translation regulation can fungal-specific aspects of the process be identified for future investigation as drug targets.